Evolution of the nematode intestine: a critical host interface Abstract More than two billion people are infected with parasitic nematodes. These pathogens are a major cause of neglected diseases that lead to mortality and diverse forms of morbidity in humans, while interfering with normal development in children. Parasitic nematodes reduce productivity of food animals and crops which are critical for economical and nutritional well-being, especially for people in developing countries. The control and treatment of these infections is challenged by the absence of vaccines, the limited choice of anthelmintics and evolution of anthelmintic resistance in these pathogens. The biological and molecular complexity of nematodes has further impeded research on development of new therapies for treatment and control. Our research focuses on the versatility of the nematode intestine as a target for new therapies. Our recent progress has established a broad and deep understanding of the molecular architecture underlying intestinal cell functions at the pan-Nematoda level. We also developed a new experimental model to investigate essential features of the nematode intestine as it relates to pan-Nematoda development of new targets for therapies to treat and control these pathogens in humans and animals. Progress to date has formed a solid foundation upon which the current proposal will capitalize in advancing capabilities to thoroughly investigate the potential of nematode intestinal functions in providing new therapies for nematode infections. Using the multi-omics resource that we have built, we will develop computational schema to identify and prioritize pan-Nematoda proteins/pathways that warrant investigation as anthelmintic targets (Aim 1). Druggable targets among prioritized proteins/pathways will be identified, followed by a systematic identification of inhibitors that can be experimentally evaluated using existing and emerging model systems (Aim 2). Aims 1 and 2 will generate the first large-scale databases of this kind for nematodes, which will have exceptionally high value for our research and that of many other investigators. Preliminary results identified microtubule-dependent apical exocytosis as a high priority process for investigation, which will be investigated in Aim 3, utilizing the Ascaris suum intestinal cell and perfusion model. This research will establish an experimental system to thoroughly investigate apical exocytosis, evaluate chemical inhibitors of this pathway and test inhibitors of other pathways identified from Aims 1 and 2. In Aim 4, progress made in preceding aims will be extended to two other core species, Haemonchus contortus and Trichuris suis, to assess the pan-Nematoda application of findings related to conserved intestinal cell processes and inhibitors. Advances are expected in establishing a new paradigm in research on parasitic nematodes that is designed to have pan-Nematoda application. Extensive databases resulting from secondary and tertiary integration of existing information offers unprecedented guidance for researchers in the field. That information will be used to guide experimental approaches for the purpose of validating predictions and testing efficacy of inhibitors that may reflect initial progress toward development of new broad spectrum anthelmintics.